Positive selection screen identifies natural product β-catenin inactivators

Many genetically validated targets in cancer, including the transcription factor β-catenin (β-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal unanticipated biological and pharmacological principles. Natural products are powerful probes because of their superior structural diversity, drug-like properties, and biological activities as compared to unoptimized synthetic compounds. We screened 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) using mammalian cells expressing an oncogenic version of β-cat fused to a suicide protein. Multiple fractions degraded the β-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active natural product from one of the latter specifically activates novel, but not classical, protein kinase Cs and thereby relocates β-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic β-cat and underscore the power of screening natural product collections with robust phenotypic assays.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-09-25
DOI
https://doi.org/10.1073/pnas.2625189123
Primary Topic
Wnt/β-catenin signaling in development and cancer
Type
article
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article

Positive selection screen identifies natural product β-catenin inactivators

Shilpa R. Shenoy, Matthew W. Boudreau, Benjamin C. Chandler, Patricia Szajner et al.
Proceedings of the National Academy of Sciences
Wnt/β-catenin signaling in development and cancer
article

Positive selection screen identifies natural product β-catenin inactivators

Shilpa R. Shenoy, Matthew W. Boudreau, Benjamin C. Chandler, Patricia Szajner, Marcelo G. Kazanietz, Rhone K. Akee, Vítor F. Freire, Tanja Grkovic, Lucero Martínez-Fructuoso, Barry R. O’Keefe, Vidyasagar Koduri, Christopher C. Thornburg, William G. Kaelin, Brian D. Peyser, Jamie L. Pfaff, Jennifer A. Smith, Dinah M. Abeja, Qinqin Jiang, Mariana Cooke, Jennifer Splaine, Benjamin L. Lampson, Jianwei Che, Katherine A. Donovan, Rohitesh Kumar, Wenyu Yu, Dongli Yu, Sophie C. Corbett
article en

Abstract

Many genetically validated targets in cancer, including the transcription factor β-catenin (β-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal unanticipated biological and pharmacological principles. Natural products are powerful probes because of their superior structural diversity, drug-like properties, and biological activities as compared to unoptimized synthetic compounds. We screened 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) using mammalian cells expressing an oncogenic version of β-cat fused to a suicide protein. Multiple fractions degraded the β-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active natural product from one of the latter specifically activates novel, but not classical, protein kinase Cs and thereby relocates β-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic β-cat and underscore the power of screening natural product collections with robust phenotypic assays.

Proceedings of the National Academy of SciencesVol. 123(39)
Broad Institute (US), Leidos (United States) (US), Brigham and Women's Hospital (US), Target (United States) (US), Howard Hughes Medical Institute (US), Harvard University (US), University of Miami (US), Dana-Farber Cancer Institute (US), National Cancer Institute (MY), Center for Cancer Research (US), Sylvester Comprehensive Cancer Center (US), Massachusetts Institute of Technology (US)
Good health and well-being
Openalex Percentile: Top 19%
Wnt/β-catenin signaling in development and cancer
DOIOpen Access PDFOpenAlex
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